PROJECT SUMMARY IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN is a progressive disease characterized by a gradually decreasing glomerular filtration rate (GFR), which results in end-stage renal disease (ESRD) in 15% to 20% of patients within 10 years of disease onset. A key observation in our understanding of the pathogenesis of IgAN is the elevated level of Gd-IgA1 in both serum and glomerular immune deposits, although the underlying molecular mechanisms are still unclear. This five-year K01 application presents a program for research and training that will support the applicant on a path towards becoming an NIH-funded independent investigator, focused on studying rare pathogenic variants in patients with IgAN and single-cell transcriptional landscape according to the level of Gd-IgA1 as an emerging indicator of biomarker of IgAN. The training plan builds on the candidate's previous training and experience, and capitalizes on a mentorship team and a research environment to foster development of the candidate's expertise in (1) clinical domain knowledge to interpret the biological and clinical impact of alterations (2) development of statistical and computational methods for problems in human genetics (3) applications of single-cell sequencing for molecular phenotyping of human immune cells relevant to glomerulonephritis and (4) responsible and ethical conduct in scientific research in human subjects. The research project will conduct diagnostic annotation of exome sequencing data in 2,500 patients with IgAN based on known Mendelian causes of kidney disease (Aim #1), discover novel genes associated with IgAN using collapsing methods for rare variants (2,500 IgAN exome data and > 6,000 control exomes) (Aim #2) and identify cell identity and transcriptional heterogeneity of IgA producing cells in IgAN patients with high or low Gd-IgA1 compared to controls using single-cell RNA-seq (Aim #3). Successful completion of this study will improve our understanding of the role of rare pathogenic variants in IgAN and facilitate clinical diagnosis and personalized disease-risk profiling. These data along with the research expertise developed through this K01 award will lead to a successful R01-level proposal with the goal of delineating pathogenesis of glomerulonephritis. The ultimate goal of this line of research is to develop genetic determinants of autoimmune-mediated renal diseases may lead to identification of biomarkers for early detection, intervention and development of novel treatments (NIDDK Strategic Research Plans for Genetics and Biological Factors).